1. Field of the Invention
The hematopoietic system is extraordinarily complex, which is not surprising in view of the central role blood cells play in the maintenance and survival of the host. One aspect of great importance is the manner in which the host protects itself from various pathogens. Two families of cells play a salient role in protecting the host, B-cells and T-cells. The mystery of how the B-cells are able to produce an extraordinary variety of immunoglobulins has been explained to a substantial degree. The germline DNA is now known to undergo rearrangements, so as to join various exons together to produce a variable region which is then joined to differing constant regions as the B-cell matures. The mechanism by which the DNA undergoes the rearrangement and the subsequent transcript is spliced to produce a messenger RNA coding for a specific immunoglobulin has been an exciting adventure demonstrating the potency of the tools afforded by the developments in molecular biology. Another class of cells important to the immune system of the host is the T-cells. These cells differ from the B-cells in that they do not secrete immunoglobulins, although they appear to have a similar range of antigenic specificities. Particularly, helper T-cells, which are involved in stimulating B-cell proliferation, can have specificity analogous to that of B-cells, with the additional requirement that they must also recognize self-major histocompatibility determinants simultaneously.
The specificity of T-cells can find application in a wide variety of situations. If one could modify a helper T-cell by introducing a foreign receptor site, one could change the response of the host to a foreign antigen. Furthermore, in many situations, it may be of interest to determine whether a cell is a helper T-cell or other type of cell. In addition, one has the opportunity to determine monoclonality in the host, which can be useful in the diagnosis of T-cell leukemias. Also, having DNA sequences which encode for portions of the T-cell antigen-specific receptor would allow for constructions involving the combination of native T-cell sequences with foreign sequences to produce novel proteins which could act as receptors. Also, antisera and monoclonal antibodies could be generated against specific parts of the protein, using either synthetic peptides or producing the protein in an expression vector. By employing hybridization with DNA sequences, subsets of T-cells may be determined as well as genetic differences and defects.
2. Description of the Prior Art
The second domain of HLA-DC has been shown to be homologous to immunoglobulin. Auffray et al., Proc. Natl. Acad. Sci. USA (1982) 79:6337-6341. The sequence about the intrachain disulfide bond in the immunoglobulin variable region is discussed by Kabat et al., in Sequences of Immunological Interest, U.S. Dept. of Health and Human Services, Washington, D.C. (1983). Cross-reactivity between B-cell anti-idiotypic antisera and T-cells is reported by Eichmann and Rajewsky, Eur. J. Immunol. (1975) 5:661-666; Binz and Wigzell, J. Exp. Med. (1975) 142:197-211, and Augustin et al., in Regulatory T Lymphocyte (eds. Pernis and Vogel) 171-184, Academic Press, N.Y., 1980. Lack of nucleotide sequence similarity between T-cell specific genes and immunoglobulin coding genes is reported by Kronenberg et al., J. Exp. Med. (1980) 152:1745-1761 and Kronenberg et al., ibid. (1983) 158:210-227, among others. Murine T-cell specific proteins are reported by Kappler et al., Cell (1983) 34:727-737 and McIntyre and Allison, ibid. (1983) 34:739-746. Allison et al., J. Immunol. (1982) 129:2293-2300; Haskins et al., J. Exp. Med. (1983) 157:1149-1169; Meuer et al., Nature (1983) 303:808-810 and Samuelson et al., Proc. Natl. Acad. Sci. USA (1983) 801:6972-6976 report the immunoprecipitation from T-cells of a disulfide linked heterodimer composed of two distinct glycoproteins of 37-50 kD in size. McIntyre and Allison, supra (1983) and Acuto et al., Cell (1983) 34:717-726 report that the heterodimer appears to have variable and constant portions by peptide map analyses. Heber-Katz et al., J. Exp. Med. (1982) 155:1086-1099 and Hedrick et al., Cell (1982) 30:141-152 report the production of MHC-restricted T-helper hybridomas, which disclosure is incorporated herein by reference. Davis et al., in B and T Cell Tumors, UCLA Symposium Vol. 24 (eds. Vitteta and Fox) 215-220, Academic Press, N.Y. 1982, report that T and B lymphocytes differ by a very small fraction of their gene expression.
Saito, Nature (1984) 309:757-762, reports a T-cell-specific cDNA clone which is rearranged in cytotoxic T-cell DNAs and has variable, constant and joining region homologous elements. Siu et al., Cell (1984) 37:393-401 and Kavaler et al., Nature (1984) 310 421-423, report the presence of diversity elements in the .beta.-chain. The .alpha.-chain of T-cell receptor molecules has been reported to be as diverse as the .beta.-chain (Kappler et al., Cell (1983) 35:295-302).